Molecular mechanisms of fentanyl mediated beta-arrestin biased signaling

doi:10.1371/journal.pcbi.1007394

	Molecular mechanisms of fentanyl mediated beta-arrestin biased signaling
	de Waal, Parker W.2,3; Shi, Jingjing 1; You, Erli 1; Wang, Xiaoxi 1; Melcher, Karsten 3; Jiang, Yi 1; Xu, H. Eric 1,3; Dickson, Bradley M.4
刊名	PLOS COMPUTATIONAL BIOLOGY
	2020-04-01
卷号	16 期号:4 页码:24
ISSN号	1553-734X
DOI	10.1371/journal.pcbi.1007394
通讯作者	Jiang, Yi(yijiang@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Dickson, Bradley M.(bradley.dickson@vai.org)
英文摘要	Author summary The global opioid crisis has drawn significant attention to the risks associated with over-use of synthetic opioids. Despite the public attention, and perhaps in-line with the profit-based incentives of the pharmaceutical industry, there is no public structure of mu-opioid receptor bound to fentanyl or fentanyl derivatives. A publicly available structure of the complex would allow open-source development of safer painkillers and synthetic antagonists. Current overdose antidotes, antagonists, require natural products in their synthesis which persists a sizable barrier to market and develop better antidotes. In this work we use advance molecular dynamics techniques to obtain the bound geometry of mu-opioid receptor with fentanyl (and derivatives) and uncovered a novel molecular switch involved in receptor activation. Based on our in-silico structure, we synthesized and tested novel compounds to validate our predicted structure. Herein we report the bound state of several dangerous fentanyl derivatives and introduce new derivatives with signaling profiles that may lead to lower risk of respiratory depression. The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or beta-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent beta-arrestin biased agonist, binds the mu-opioid receptor (mu OR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. Following an in-silico derived hypothesis we found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce beta-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate an activation mechanism where the n-aniline ring of fentanyl mediates mu OR beta-arrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated beta-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.
资助项目	Van Andel Institute Graduate School ; Jay and Betty Van Andel Foundation ; National Natural Science Foundation[31770796] ; National Science and Technology Major Project[2018ZX09711002] ; K.C. Wong Education Foundation
WOS关键词	MU-OPIOID-RECEPTOR ; CRYSTAL-STRUCTURE ; DYNAMICS SIMULATIONS ; STRUCTURAL INSIGHTS ; MICE LACKING ; ANALOGS ; BINDING ; DISCOVERY ; ANALGESIA ; EFFICACY
WOS研究方向	Biochemistry & Molecular Biology ; Mathematical & Computational Biology
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000531366700071
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280276]
专题	中国科学院上海药物研究所
通讯作者	Jiang, Yi; Xu, H. Eric; Dickson, Bradley M.
作者单位	1.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 2.DE Shaw Res, New York, NY USA 3.Van Andel Res Inst, Ctr Canc & Cell Biol, Innovat & Integrat Program, Grand Rapids, MI 49503 USA 4.Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 USA
推荐引用方式 GB/T 7714	de Waal, Parker W.,Shi, Jingjing,You, Erli,et al. Molecular mechanisms of fentanyl mediated beta-arrestin biased signaling[J]. PLOS COMPUTATIONAL BIOLOGY,2020,16(4):24.
APA	de Waal, Parker W..,Shi, Jingjing.,You, Erli.,Wang, Xiaoxi.,Melcher, Karsten.,...&Dickson, Bradley M..(2020).Molecular mechanisms of fentanyl mediated beta-arrestin biased signaling.PLOS COMPUTATIONAL BIOLOGY,16(4),24.
MLA	de Waal, Parker W.,et al."Molecular mechanisms of fentanyl mediated beta-arrestin biased signaling".PLOS COMPUTATIONAL BIOLOGY 16.4(2020):24.